Evaluation of a novel hinge and co-stimulatory domain in BCMA-targeted chimeric antigen receptor T cells.

The field of chimeric antigen receptor (CAR)-T-cell immunotherapy has evolved tremendously over the past decades. One of the milestones in CAR development was the incorporation of co-stimulatory domains, providing the necessary signaling to trigger full T-cell activation. Given their improved performance, these so-called second-generation CAR-T cells equiped with CD28- or 4-1BB -based intracellular domains dominate the clinical trial landscape. For multiple myeloma, the second most common type of blood cancer, early-phase clinical trials with B-cell maturation antigen (BCMA)-targeted CAR-T cells have demonstrated promising results, but relapses are frequently observed. Therefore, a great deal of research attention is currently being paid at improving the efficacy of the CAR-T cells. In the proposed project, we want to evaluate the potential of CD26 as a co-stimulatory domain in BCMA-targeted CARs. CD26 has been shown to improve persistence and anti-tumor activity of T cells, and is associated with a memory phenotype. In addition, the impact of the hinge domain on CAR-T-cell efficacy has been poorly studied, although the hinge domain has been shown to be important for antigen recognition. Therefore, we developed a novel 4-1BB-based hinge in collaboration with colleagues at Fudan University, Shanghai, China. This new hinge was already validated in the context of anti-HER-2, -GPC3 and -CD19 CAR-T cells, and will be further evaluated here in multiple myeloma.

Keywords:CANCER VACCINES, T-CELLS, CELLULAR IMMUNE RESPONSES, CHIMERIC ANTIGEN RECEPTORS

Disciplines:Hematology, Cancer therapy